Neurocognitive outcomes in moderately preterm born adolescents.

BACKGROUND: Early preterm (EP) born children are at risk of neurocognitive impairments persisting into adulthood. Less is known about moderately to late (MLP) preterm born children, especially after early childhood. The aim of this study was to assess neurocognitive functioning of MLP adolescents regarding intelligence, executive and attentional functioning, compared with EP and full-term (FT) adolescents. METHODS: This study was part of the Longitudinal Preterm Outcome Project (LOLLIPOP), a large community-based observational cohort study. In total 294 children (81 EP, 130 MLP, and 83 FT) were tested at age 14 to 16 years, regarding intelligence, speed of processing, attention, and executive functions. We used the Dutch version of the Wechsler Intelligence Scale for Children-Third Edition-Dutch Version (WISC-III-NL), the Test of Everyday Attention for Children, and the Behavioural Assessment of the Dysexecutive Syndrome for Children. We assessed differences between preterm-born groups with the FT group as a reference. RESULTS: Compared to the FT group, MLP adolescents scored significantly lower on two subtasks of the WISC-III-NL, i.e. Similarities and Symbol Search. EP adolescents performed significantly lower on all neuropsychological tests than their FT peers, except for the subtask Vocabulary. The MLP adolescents scored in between FT and EP adolescents on all tasks, except for three WISC-III-NL subtasks. CONCLUSIONS: Neurocognitive outcomes of MLP adolescents fell mostly in between outcomes of their EP and FT peers. MLPs generally performed on a low-average to average level, and appeared susceptible to a variety of moderate neurodevelopmental problems at adolescent age, which deserves attention in clinical practice.

Dyskinesia Impairment Scale scores in Dutch pre-school children after neonatal therapeutic hypothermia.

BACKGROUND: Neonatal therapeutic hypothermia (TH) can ameliorate or prevent the development of dyskinetic cerebral palsy (CP) after hypoxic-ischemic encephalopathy (HIE). The Dyskinesia Impairment Scale (DIS) was recently launched to quantify dyskinetic (dystonic and choreatic) motor features in patients with CP. In TH treated children, who are at risk of developing dyskinetic CP, we aimed to determine DIS-scores at pre-school age. METHOD: In 21 Dutch pre-school children (3-6 years of age) who had received TH according to the Dutch-Flemish treatment protocol, we determined DIS-scores. We associated DIS-scores with 1. age-matched control values (Kuiper et al., 2018) [1], and 2. previously reported DIS-score range in dyskinetic CP (Monbaliu E et al., 2015). RESULTS: The motor phenotype was determined as: normal (n = 18/21), mildly impaired (reduced coordination (n = 2/21)) and abnormal (dyskinetic CP; n = 1/21). In absence of CP (n = 20/21), DIS-scores were lower (more favorable) than in dyskinetic CP, without any overlapping group scores (mean difference: 71 points; p < .05). However, the obtained DIS-scores were still higher than previously reported in healthy age-matched controls (mean difference: 14 points; p < .05). There was an association between DIS-scores and retrospective neonatal MRI (basal ganglia and thalamus injury on diffusion weighted imaging (DWI)) and (a)EEG parameters (p < .05). CONCLUSION: In the vast majority (95%) of Dutch TH-HIE treated pre-school children, the phenotypic motor outcome was favorable. However, DIS-scores were moderately increased compared with healthy age-matched controls. Future studies may elucidate the significance of moderately increased DIS-scores should to further extent.

Time to full enteral feeding after necrotizing enterocolitis in preterm-born children is related to neurodevelopment at 2-3 years of age.

BACKGROUND: Necrotizing enterocolitis (NEC) is associated with poorer neurodevelopment. It is, however, unclear which factors besides surgery affect neurodevelopment in preterm-born children surviving NEC. AIMS: We determined whether time to full enteral feeding (FEFt) and post-NEC complications after NEC were associated with neurodevelopment. STUDY DESIGN: Prospective observational cohort study. SUBJECTS: Two to three year old preterm-born children who survived NEC (Bells stage ≥ 2). We categorized children in two groups, one group shorter and equal and one group longer than the group's median FEFt. Post-NEC complications included recurrent NEC and/or post-NEC stricture. OUTCOME MEASURES: Bayley Scales of Infants and Toddler Development III (Bayley-III) and Child Behavior Checklist (CBCL). Associations between Bayley-III and CBCL scores with FEFt and Post-NEC complications were determined using linear regression analyses, adjusted for severity of illness and potential confounders. RESULTS: We included 44 children, median gestational age of 27.9 [IQR: 26.7-29.3] weeks, birth weight 1148 [IQR: 810-1461] grams. Median FEFt after NEC was 20 [IQR: 16-30] days. Median follow-up age was 25.7 [IQR: 24.8-33.5] months. FEFt > 20 days was associated with lower cognitive and lower motor composite scores of the Bayley-III (B: -8.6, 95% CI -16.7 to -0.4, and B: -9.0, 95% CI, -16.7 to -1.4). FEFt was not associated with CBCL scores. Post-NEC complications (n = 11) were not associated with Bayley-III scores nor with CBCL scores. CONCLUSIONS: Prolonged FEFt after NEC in preterm-born children surviving NEC is associated with lower cognitive and lower motor composite scores at the age of 2-3 years. These results show the importance of limiting the duration of the nil per mouth regimen if and when possible.

Necrotizing Enterocolitis Associated with Congenital Heart Disease: a Different Entity?

BACKGROUND: Necrotizing enterocolitis (NEC) predominantly occurs in preterm infants (PT-NEC). In term neonates, NEC occurs more frequently when a congenital heart disease is present (CHDNEC). Our aim was to evaluate differences and similarities in disease characteristics of PT-NEC versus CHD-NEC. METHODS: In this retrospective case-control study we identified all CHD infants who developed NEC Bell's stage ≥2 in our center from 2004 to 2014. We randomly selected (1:2 ratio) PT-NEC infants from the same period. Biochemical and clinical variables were retrieved from patient files. RESULTS: We found 18 CHD-NEC infants and selected 36 PT-NEC infants (gestational age 28.3 [25-35.6] weeks vs. 38.6 [31.7-40.7] weeks). Postnatal age at onset was significantly lower in CHD-NEC patients (4 [2-24] vs. 11 [4-41] days, p < 0.001). Lowest pH levels were lower (7.21 [7.01-7.47] vs. 7.27 [6.68-7.39], p = 0.02), and highest CRP levels were higher (112.5 mg/L [5.0-425.0] vs. 66.0 [5.2-189.0], p = 0.05) in PT-NEC vs. CHD-NEC. Anatomic localisation of the disease differed: the colon was significantly more often involved in CHD-NEC versus PT-NEC (86% vs. 33%, p = 0.03). Mortality caused by NEC was not different (22% vs. 11%, p = 0.47). CONCLUSION: While outcome of NEC in both groups is similar, the predominant NEC localisation differed between CHD-NEC and PT-NEC patients. This suggests that both variants of the disease have a different underlying pathophysiological mechanism that predisposes different intestinal regions to develop NEC. TYPE OF STUDY: Retrospective Case-Control Study. LEVEL OF EVIDENCE: Level III.

Growth patterns and cerebroplacental hemodynamics in fetuses with congenital heart disease.

OBJECTIVES: Congenital heart disease (CHD) has been associated with reduced fetal head circumference (HC), although the underlying pathophysiology remains undetermined. We aimed to define trends in fetal growth and cerebroplacental Doppler flow, and to investigate their relationship, in fetuses with CHD. METHODS: This was a retrospective study in two fetal medicine units in The Netherlands. We included all fetuses with CHD in whom Doppler flow patterns (middle cerebral artery (MCA) pulsatility index (PI), umbilical artery (UA) PI and cerebroplacental ratio (CPR)) and biometry (HC and abdominal circumference (AC)) had been measured serially after 19 weeks' gestation between January 2010 and November 2016. Fetuses were categorized into three groups based on the expected cerebral arterial oxygen saturation of their particular type of CHD: normal; mild to moderately reduced; severely reduced. Trends over time in Z-scores were analyzed using a linear mixed-effects model. RESULTS: A total of 181 fetuses fulfilled the inclusion criteria. Expected cerebral arterial oxygen saturation in CHD was classified as normal in 44 cases, mild to moderately reduced in 84 and severely reduced in 53. In the cohort overall, average trends over time were significant for both HC and AC Z-scores. HC Z-scores showed a tendency to decrease until 23 weeks, then to increase until 33 weeks, followed by another decrease in the late third trimester. AC Z-scores increased progressively with advancing gestation. MCA-PI and UA-PI Z-scores showed significant trends throughout pregnancy, but CPR Z-scores did not. There were no associations between expected cerebral arterial oxygen saturation and fetal growth. Average trends in MCA-PI Z-scores were significantly different between the three subgroups, whereas those in UA-PI Z-scores and in CPR Z-scores were similar between the subgroups. There was no significant association between MCA-PI and HC Z-scores. CONCLUSIONS: Fetal biometry and Doppler flow patterns are within normal range in fetuses with CHD, but show trends over time. Head growth in fetuses with CHD is not associated with cerebral blood flow pattern or placental function and HC is not influenced by the cerebral arterial oxygen saturation. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Amplitude-Integrated EEG and Cerebral Near-Infrared Spectroscopy in Cooled, Asphyxiated Infants.

OBJECTIVE: To assess the predictive value of amplitude-integrated electroencephalography EEG (aEEG) and near-infrared spectroscopy (NIRS) during therapeutic hypothermia. PATIENTS AND METHODS: We studied 39 cooled, asphyxiated infants. We assessed aEEG and calculated mean regional cerebral oxygen saturation (rcSO2) during and after treatment. At 30 months, we performed a neurological examination and administered the Bayley Scales of Infant and Toddler Development, 3rd edition. We calculated the odds ratios (ORs) of abnormal aEEG and rcSO2 for severely abnormal outcome. RESULTS: At 6 and 12 hours, severely abnormal aEEGs predicted severely abnormal outcomes (OR, 7.7 [95% confidence interval, CI, 1.39-42.6] and 24.4 [95% CI 4.2-143] respectively), as did epileptic activity (OR 28.9, 4.6-183). During the first 48 hours, rcSO2 was not associated with outcome, but at 72 hours after birth and after rewarming it was, with ORs for severely abnormal outcomes of 12.8 (1.31-124) and 21.6 (1.05-189), respectively. In multivariate analyses, aEEG and rcSO2 remained independently predictive in the model at 48 hours and significantly from 72 hours after birth onward. CONCLUSION: aEEG was a strong predictor of adverse outcome. After 48 hours of cooling, a higher rcSO2 was associated with a severely abnormal outcome, adding to the predictive value of aEEG in cooled, asphyxiated infants.

The prevalence of feeding problems in children formerly treated in a neonatal intensive care unit.

OBJECTIVE: To determine the prevalence of oral feeding problems in neonatal intensive care unit (NICU) graduates at 1 to 2 years, and to identify clinical risk factors during NICU admission. STUDY DESIGN: Observational cohort study of 378 children, who received level III/IV NICU care for 4 days or more in 2011 to 2012, chromosomal abnormalities excluded. We detected feeding problems in four gestational age (GA) groups (<28, 28 to 31, 32 to 36 weeks, and term-borns) using the Dutch standardized Screeningslijst Eetgedrag Peuters, and collected clinical factors for logistic regression analyses. RESULTS: The prevalence of feeding problems was higher in NICU (20.4%) than in reference (15.0%) population (P=0.024), but similar for all GA groups (P=0.468). Prolonged tube feeding, that is, >30 days (odds ratio (OR) 2.50, confidence interval (CI) 1.13 to 5.56) and being born small for GA (OR 4.79, CI 1.64 to 14.03) were the most prevalent risk factors in children with GA ⩾32 and GA <32 weeks, respectively. CONCLUSION: Feeding problems are more prevalent in NICU graduates, with prolonged tube feeding as most important risk factor.

Identification of bacterial invasion in necrotizing enterocolitis specimens using fluorescent in situ hybridization.

OBJECTIVE: Investigation of bacterial invasion into the intestinal wall in necrotizing enterocolitis (NEC) specimens. STUDY DESIGN: We compared 43 surgical NEC specimens with 43 age-matched controls. We used fluorescent in situ hybridization (FISH), a universal bacterial probe together with species-specific probes for Clostridium spp., Enterobacteriaceae, bacteroides and enterococci/lactobacilli. We used a FISH scoring system to reveal invasion of the intestinal wall, in which 1 represented no colonies and 4 invasion of the intestinal wall. RESULTS: We observed invasion of the intestinal wall in 22/43 of the most affected NEC tissue samples as compared with 16/43 in the least affected NEC tissue samples (P=0.03). A FISH score of 4 was reached in 7/43 control cases. Enterobacteriaceae dominated the NEC specimens. Clostridium spp. were detected occasionally in NEC samples. CONCLUSION: Bacterial invasion of the intestinal wall is more present in most affected NEC tissue samples compared with least affected NEC tissue samples or controls. Enterobacteriaceae are prevalent in advanced NEC.

White Matter Injury and General Movements in High-Risk Preterm Infants.

BACKGROUND AND PURPOSE: Very preterm infants (birth weight, <1500 g) are at increased risk of cognitive and motor impairment, including cerebral palsy. These adverse neurodevelopmental outcomes are associated with white matter abnormalities on MR imaging at term-equivalent age. Cerebral palsy has been predicted by analysis of spontaneous movements in the infant termed "General Movement Assessment." The goal of this study was to determine the utility of General Movement Assessment in predicting adverse cognitive, language, and motor outcomes in very preterm infants and to identify brain imaging markers associated with both adverse outcomes and aberrant general movements. MATERIALS AND METHODS: In this prospective study of 47 preterm infants of 24-30 weeks' gestation, brain MR imaging was performed at term-equivalent age. Infants underwent T1- and T2-weighted imaging for volumetric analysis and DTI. General movements were assessed at 10-15 weeks' postterm age, and neurodevelopmental outcomes were evaluated at 2 years by using the Bayley Scales of Infant and Toddler Development III. RESULTS: Nine infants had aberrant general movements and were more likely to have adverse neurodevelopmental outcomes, compared with infants with normal movements. In infants with aberrant movements, Tract-Based Spatial Statistics analysis identified significantly lower fractional anisotropy in widespread white matter tracts, including the corpus callosum, inferior longitudinal and fronto-occipital fasciculi, internal capsule, and optic radiation. The subset of infants having both aberrant movements and abnormal neurodevelopmental outcomes in cognitive, language, and motor skills had significantly lower fractional anisotropy in specific brain regions. CONCLUSIONS: Aberrant general movements at 10-15 weeks' postterm are associated with adverse neurodevelopmental outcomes and specific white matter microstructure abnormalities for cognitive, language, and motor delays.

Relationship between general movements in neonates who were growth restricted in utero and prenatal Doppler flow patterns.

OBJECTIVE: To investigate whether Doppler pulsatility indices (PIs) of the fetal circulation in cases of fetal growth restriction (FGR) are associated with the general movements (GMs) of the neonate after birth. METHODS: This was a prospective observational cohort study including pregnancies with FGR diagnosed between June 2012 and September 2014. A diagnosis of FGR was based on an abdominal circumference or estimated fetal weight < 10th percentile (in conjuction with abnormal Doppler) or declining fetal growth of at least 30 percentiles with respect to previous size measurements. Doppler parameters of the umbilical artery (UA), fetal middle cerebral artery (MCA) and ductus venosus (DV) were measured maximally 1 week prior to delivery. Cerebroplacental ratio (CPR) was calculated as MCA-PI divided by UA-PI. We assessed the quality of neonatal GMs 7 days after birth, around the due date if cases were born preterm, and at 3 months post-term. We performed a detailed analysis of the motor repertoire by calculating a motor optimality score (MOS). RESULTS: Forty-eight FGR cases were included with a median gestational age at delivery of 35 (range, 26-40) weeks. UA-PI, MCA-PI and CPR correlated strongly (ρ, -0.374 to 0.472; P < 0.01) with the MOS on day 7 after birth, but DV-PI did not. Doppler PI measurements did not correlate with MOS at 3 months post-term. CONCLUSION: Fetal arterial Doppler measurements are associated with the quality of neonatal GMs 1 week after birth, but this association is no longer evident at 3 months post-term. Brain sparing in particular is associated strongly with GMs of an abnormal quality. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Correlation between Doppler flow patterns in growth-restricted fetuses and neonatal circulation.

OBJECTIVES: To investigate whether prenatal Doppler parameters in growth-restricted fetuses are correlated with neonatal circulatory changes. METHODS: In 43 cases of suspected fetal growth restriction (FGR), serial Doppler measurements of umbilical artery (UA) and middle cerebral artery (MCA) pulsatility index (PI) were performed. The last measurement, closest to delivery (< 1 week before birth), was used for analysis. Neonatal circulation was assessed for 2 h/day on Days 1-5, 8 and 15 by near-infrared spectroscopy (NIRS) of the cerebral, renal and splanchnic regions. We calculated fractional tissue oxygen extraction (FTOE) as: (arterial oxygen saturation - NIRS value)/arterial oxygen saturation. The following ratios were calculated: cerebroplacental ratio (CPR; MCA-PI/UA-PI), cerebrorenal ratio (CRR; cerebral/renal FTOE) and cerebrosplanchnic ratio (CSR; cerebral/splanchnic FTOE). Spearman's rank correlation coefficient (ρ) was calculated between prenatal Doppler parameters and neonatal NIRS variables. These analyses were carried out for the entire group, and separately for cases of early FGR (delivered < 34 weeks) and late FGR (≥ 34 weeks). RESULTS: Fetal Doppler parameters correlated with neonatal NIRS variables on Days 1-3: UA-PI correlated with renal FTOE (Day 1: ρ = 0.454, P < 0.01) and CRR (Day 1: ρ = -0.517, P < 0.001). MCA-PI correlated with cerebral FTOE on Day 2 (ρ = 0.469, P < 0.01), approached statistical significance on Day 3 but was not correlated on Day 1. CPR correlated with CRR (Day 1: ρ = 0.474, P < 0.01). Most associations lost their statistical significance when early and late FGR subgroups were considered separately. CONCLUSION: Low MCA-PI and low CPR, indicating brain sparing before birth, are associated with low CRR after birth, indicating relatively greater blood flow to the cerebrum than to the renal region. Based on the results of this study, it could be speculated that if brain sparing is present in the fetal circulation, it persists during the first 3 days after birth. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Risk factors associated with postnecrotizing enterocolitis strictures in infants.

INTRODUCTION: Survivors of necrotizing enterocolitis (NEC) often develop a post-NEC intestinal stricture, causing severe and prolonged morbidity. OBJECTIVES: We first aimed to determine the incidence of post-NEC strictures. Second, we aimed to determine risk factors associated with intestinal post-NEC strictures. MATERIALS AND METHODS: A total of 441 patients diagnosed with NEC Bell's stage ≥2 were retrospectively included in three academic pediatric surgical centers between January 2005 and January 2013. Clinical data were related to the occurrence of intestinal post-NEC strictures. Post-NEC strictures were defined as clinically relevant strictures with a radiological and/or surgical confirmation of this post-NEC stricture. RESULTS: The median gestational age of the 337 survivors of the acute phase of NEC was 29weeks (range 24-41) and median birth weight was 1130g (range 410-4130). Of the survivors, 37 (17%) medically treated NEC patients developed a post-NEC strictures versus 27 surgically treated NEC patients (24%; p=0.001). Highest C-reactive protein (CRP) level measured during the NEC episode was associated with the development of post-NEC strictures (OR 1.20, 95% confidence interval 1.11-1.32; p=0.03). No post-NEC strictures were detected in patients with CRP levels <46mg/L. CONCLUSION: This multicenter retrospective cohort study demonstrates an overall incidence of clinical relevant post-NEC strictures of 19%, with a higher rate (24%) in NEC cases treated surgically. Increased CRP levels during the NEC episode were associated with the development of post-NEC strictures.

Bloodstream infections during the onset of necrotizing enterocolitis and their relation with the pro-inflammatory response, gut wall integrity and severity of disease in NEC.

INTRODUCTION: Bacterial involvement is believed to play a pivotal role in the development and disease outcome of NEC. However, whether a bloodstream infection (BSI) predisposes to NEC (e.g. by activating the pro-inflammatory response) or result from the loss of gut wall integrity during NEC development is a longstanding question. OBJECTIVE: We hypothesize that the occurrence of a BSI plays a complementary role in the pathogenesis of NEC. The first aim of the study was to correlate the occurrence of a BSI during the early phase of NEC with intestinal fatty acid-binding protein (I-FABP) levels, as a marker for loss of gut wall integrity owing to mucosal damage, and Interleukin (IL)-8 levels, as a biomarker for the pro-inflammatory cascade in NEC. The second aim of the study was to investigate the relation between the occurrence of a BSI and disease outcome. MATERIAL AND METHODS: We combined data from prospective trials from two large academic pediatric surgical centers. Thirty-eight neonates with NEC, 5 neonates with bacterial sepsis, and 14 controls were included. RESULTS: BSIs occurred in 10/38 (26%) neonates at NEC onset. No association between the occurrence of BSIs and I-FABP levels in plasma (cohort 1: median 11ng/mL (range 0.8-298), cohort 2: median 6.8ng/mL (range 1.3-15)) was found in NEC patients (cohort 1: p=0.41; cohort 2: p=0.90). In addition, the occurrence of BSIs did not correlate with IL-8 (median 1562pg/mL (range 150-7,500); p=0.99). While the occurrence of a BSI was not correlated with Bell's stage (p=0.85), mortality was higher in patients with a BSI (p=0.005). CONCLUSION: The low incidence of BSIs and the absent association of both the markers for loss of gut wall integrity and the pro-inflammatory response during the early phase of NEC, support the hypothesis that the presence of a BSI does not precede NEC.

Intestinal fatty acid-binding protein levels in Necrotizing Enterocolitis correlate with extent of necrotic bowel: results from a multicenter study.

BACKGROUND: Intestinal fatty acid-binding protein (I-FABP) is considered as a specific marker for enterocyte damage in necrotizing enterocolitis (NEC). OBJECTIVE: The purpose of this study was to evaluate the association of plasma and urinary I-FABP levels with the extent of macroscopic intestinal necrosis in surgical NEC. METHODS: We combined data from prospective trials from two large academic pediatric surgical centers. Nine and 10 infants with surgical NEC were included, respectively. Plasma and urinary of I-FABP at disease onset were correlated with the length of intestinal resection during laparotomy. RESULTS: Median length of bowel resection was 10cm (range 2.5-50) and 17cm (range 0-51), respectively. Median I-FABP levels were 53ng/mL (range 6.3-370) and 4.2ng/mL (range 1.1-15.4) in plasma in cohort 1 respectively cohort 2 and 611ng/mL (range 3-23,336) in urine. The length of bowel resection significantly correlated with I-FABP levels in plasma (Rho 0.68; p=0.04 and Rho 0.66;p=0.04) and in urine (Rho 0.92; p=0.001). CONCLUSION: This 'proof of concept' study demonstrates that plasma and urine I-FABP levels at disease onset was strongly associated with the length of intestinal resection in surgical NEC. This offers further evidence that I-FABP levels are a promising biomarker for assessing intestinal necrosis in infants with advanced NEC.

Placental pathology and neurological morbidity in preterm infants during the first two weeks after birth.

BACKGROUND: The placenta plays a crucial role during pregnancy and dysfunction causes long-term neurological problems. Identifying placenta-related risks for neurological problems shortly after birth may provide clues for early interventions aiming to improve neurological outcome. OBJECTIVE: To determine the association between placental pathology and neurological morbidity in preterm infants during the first two weeks after birth. STUDY DESIGN: Placentas of 52 singleton, preterm infants (GA: 25-31weeks, BW: 560-2250 grammes) were examined for histopathology. The infants' neurological condition shortly after birth was determined by assessing the quality of their general movements (GMs): normal, abnormal, or hypokinetic, on days 5, 8, and 15. A motor optimality score (MOS) was also assigned. RESULTS: Examination of the placentas revealed maternal vascular underperfusion (n=29), ascending intrauterine infection (AIUI) (n=19), villitis of unknown aetiology (n=6), chronic deciduitis (n=11), foetal thrombotic vasculopathy (FTV) (n=9), and elevated nucleated red blood cells (NRBCs) as a marker for foetal hypoxia (n=7). None of the placental lesions were significantly associated with the quality of GMs or MOS. CONCLUSIONS: This study indicated that placental lesions were not associated with infants' neurological condition as measured by the quality of their general movements during the first two weeks after birth.

Rapid target allopurinol concentrations in the hypoxic fetus after maternal administration during labour.

OBJECTIVE: Perinatal hypoxia-induced free radical formation is an important cause of hypoxic-ischaemic encephalopathy and subsequent neurodevelopmental disabilities. Allopurinol reduces the formation of free radicals, which potentially limits hypoxia-induced brain damage. We investigated placental transfer and safety of allopurinol after maternal allopurinol treatment during labour to evaluate its potential role as a neuroprotective agent in suspected fetal hypoxia. DESIGN: We used data from a randomised, double-blind multicentre trial comparing maternal allopurinol versus placebo in case of imminent fetal hypoxia (NCT00189007). PATIENTS: We studied 58 women in labour at term, with suspected fetal hypoxia prompting immediate delivery, in the intervention arm of the study. SETTING: Delivery rooms of 11 Dutch hospitals. INTERVENTION: 500 mg allopurinol, intravenously to the mother, immediately prior to delivery. MAIN OUTCOME MEASURES: Drug disposition (maternal plasma concentrations, cord blood concentrations) and drug safety (maternal and fetal adverse events). RESULTS: Within 5 min after the end of maternal allopurinol infusion, target plasma concentrations of allopurinol of ≥2 mg/L were present in cord blood. Of all analysed cord blood samples, 95% (52/55) had a target allopurinol plasma concentration at the moment of delivery. No adverse events were observed in the neonates. Two mothers had a red and/or painful arm during infusion. CONCLUSIONS: A dose of 500 mg intravenous allopurinol rapidly crosses the placenta and provides target concentrations in 95% of the fetuses at the moment of delivery, which makes it potentially useful as a neuroprotective agent in perinatology with very little side effects. TRIAL REGISTRATION: The study is registered in the Dutch Trial Register (NTR1383) and the Clinical Trials protocol registration system (NCT00189007).

The effect of preimplantation genetic screening on neurological, cognitive and behavioural development in 4-year-old children: follow-up of a RCT.

STUDY QUESTION: Does embryo biopsy inherent to preimplantation genetic screening (PGS) affect neurological, cognitive and behavioural development of 4-year-old children? SUMMARY ANSWER: PGS does not seem to affect neurological, cognitive and behavioural development of 4-year-old singletons; however, our data suggest that it may be associated with altered neurodevelopment in twins. WHAT IS KNOWN ALREADY: Evidence concerning the safety of PGS on neurodevelopmental outcome in offspring is scarce. The present study provides information on neurodevelopmental, cognitive and behavioural outcome of 4-year-old PGS offspring. STUDY DESIGN, SIZE, DURATION: A prospective, assessor-blinded follow-up study of children born to women who participated in a multi-centre RCT on the effect of IVF with or without PGS. PARTICIPANTS/MATERIALS, SETTING, METHODS: At 4 years, 49 children (31 singletons, 9 sets of twins) born following IVF with PGS and 64 children (42 singletons, 11 sets of twins) born following IVF without PGS (controls) were assessed (post-natal attrition 18%). Neurological development was evaluated with the standardized, age-specific and sensitive neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the rate of adverse neurological outcome. Primary outcome was the fluency score, as fluency of movements is easily reduced by subtle dysfunction of the brain. Cognitive development was evaluated with the Kaufman Assessment Battery for Children; behavioural development was evaluated with the Child Behavior Checklist. The effect of PGS was analysed with a mixed effects model. MAIN RESULTS AND THE ROLE OF CHANCE: Based on the intention to treat analysis, neurodevelopmental outcome of PGS children was similar to that of controls. However, additional analyses indicated that PGS affected neurodevelopmental outcome of twins in a different way than that of singletons. The fluency score of singletons born following PGS was similar to that of control singletons [mean values, 95% confidence intervals (CIs): 12.2 (11.5;12.8) and 12.2 (11.6;12.8)], respectively, P = 0.977) that was also true for the other neurodevelopmental parameters. The fluency score of PGS twins was significantly lower than that of control twins [mean values, 95% CIs: 10.6 (9.8;11.3) and 12.3 (11.5;13.1)], respectively, P = 0.001); the same was true for the NOS. In addition, PGS in twins was associated with a higher sequential intelligence quotient score. On the other hand, other neurodevelopmental parameters were similar for PGS twins and control twins. Post hoc sample size calculation for the primary outcome parameter, the fluency score, indicated that the study groups, including the subgroups of singletons and twins, were adequately powered. LIMITATIONS, REASONS FOR CAUTION: We assessed singletons and twins who contributed to the generalizability of the study. A limitation of our study is the relative small size of our study groups and the selective dropout in both groups (dropouts PGS group: higher gestational age; control group: less well-educated parents). These preclude the conclusion that PGS per se is not associated with neurodevelopmental, cognitive and behavioural problems in singletons and the conclusion that PGS is associated with altered neurodevelopmental outcome in twins. WIDER IMPLICATIONS OF THE FINDINGS: The need for careful long-term monitoring of children born following embryo biopsy remains, as it is still applied in the form of PGD and it is still unknown whether embryo biopsy affects long-term neurodevelopmental outcome.

The impact of IVF/ICSI on parental well-being and anxiety 1 year after childbirth.

BACKGROUND: More couples are delaying childbirth resulting in an increase of age-related subfertility in women. Subfertility and assisted reproductive technology (ART) treatments may affect couples' psychological well-being. The aim of the present study was to investigate whether factors related to IVF/ICSI affect anxiety and mental health in couples 1 year after childbirth. METHOD: In this cohort study, we included couples with a singleton pregnancy following IVF/ICSI treatment (n=113) and subfertile couples who naturally conceived (NC; n=83). Parental trait anxiety (Dutch version of the Spielberger State-Trait Anxiety Inventory) and mental health (Dutch version of General Health Questionnaire) were assessed 1 year after childbirth. The influence of fertility-related factors was analyzed with logistic regression analyses. RESULTS: One hundred and ninety-six couples participated, 93% of those eligible. Trait anxiety and mental health were similar in IVF/ICSI and NC groups. However, NC fathers had more often mental health scores in the clinical range (21%) than fathers in the IVF/ICSI group (9%). The risk of having a trait anxiety or mental health score in the clinical range was reduced by the presence of one of the following factors: for females a higher number of IVF/ICSI treatment cycles, and a maternal cause of subfertility, for males having been treated by IVF/ICSI and a longer time to pregnancy. CONCLUSIONS: The present study indicates (i) that IVF/ICSI treatment is not associated with an increase in clinically relevant Spielberger State-Trait Anxiety Inventory and General Health Questionnaire scores in parents 1 year after childbirth and (ii) a higher number of IVF/ICSI treatment cycles and a longer time to pregnancy were associated with less trait anxiety and better mental health. A limitation of the study is the absence of mental health and trait anxiety data at baseline.

Parental psychological distress and anxiety after a successful IVF/ICSI procedure with and without preimplantation genetic screening: follow-up of a randomised controlled trial.

BACKGROUND: Infertility treatment has an acknowledged psychological impact on women and their partners; however, information about the development of parental well-being after child birth is inconclusive. Preimplantation genetic screening (PGS) has been suggested to increase the efficacy of infertility treatments, but the effect it may have on parental well-being is unknown. AIM: To evaluate parental distress and anxiety at one and two years after successful infertility treatment and to explore variables that might affect parental outcome, including PGS and child behaviour. STUDY DESIGN: Follow-up of a randomised controlled trial (RCT) on the efficacy of PGS. SUBJECTS: Parents (n=101) that successfully underwent IVF/ICSI with or without PGS. OUTCOME MEASURES: At one and two years, parental distress and anxiety were assessed with the General Health Questionnaire 30 and State Trait Anxiety Inventory, respectively. At two years, child development and behaviour were assessed with the Dutch Bayley Scales of Infant Development-II and the Child Behaviour Checklist 1½-5, respectively. RESULTS: PGS had no effect on parental distress or anxiety. Child behaviour problems were associated with parental distress and anxiety. There was a main effect of time on parental distress, with distress levels decreasing over time. CONCLUSIONS: We found no objection to PGS related to parental psychological distress and anxiety. When parental psychological problems are present after infertility treatment, the results of this study could be useful to support counselling.

Placental pathology is associated with illness severity in preterm infants in the first twenty-four hours after birth.

BACKGROUND: Placental pathology is associated with long-term neurological morbidity. Little is known about the association of placental pathology and illness severity directly after birth in preterm infants. OBJECTIVE: To determine the association between placental pathology and illness severity in preterm infants during the first 24 h after birth. STUDY DESIGN: Placentas of 40 preterm infants, born after singleton pregnancies (gestational age 25.4-31.7 weeks, birth weight 560-2250 g) were assessed for histopathology. Illness severity was measured using the Score of Neonatal Acute Physiology Perinatal Extension (SNAPPE). A high SNAPPE reflects high illness severity. RESULTS: Examination of the 40 placentas revealed: pathology consistent with maternal vascular underperfusion (MVU) (n=24), ascending intrauterine infection (AIUI) (n=17), villitis of unknown aetiology (VUE) (n=6), foetal thrombotic vasculopathy (FTV) (n=6), elevated nucleated red blood cells (NRBCs) (n=6), and chronic deciduitis (n=10). SNAPPE ranged from 1 to 53 (median 10). Infants with elevated NRBCs had a higher SNAPPE than infants without elevated NRBCs (median 30 vs. 10, p=0.014). The same was found for the presence of FTV (median 30 vs. 10, p=0.019). No relation existed between SNAPPE and the other placental pathologies. CONCLUSIONS: Elevated NRBCs and FTV were associated with higher illness severity during the first 24 h after birth in preterm infants. Ascending intrauterine infection was not associated with high illness severity.